Tissue Use for Repair of Injury

ABSTRACT

The present disclosure describes methods of treating an injury in a subject using placental tissue streamers, engineered tissue placental tissue hybrids, suture placental tissue hybrids, placental tissue patch hybrids, and tissue hybrids, and the use of these compositions to repair, treat, or support an injury or degenerative process in a subject.

PRIORITY

This application is a continuation of U.S. Ser. No. 15/683,868, filed onAug. 23, 2018, which claims the benefit of U.S. Ser. No. 62/378,740filed on Aug. 24, 2016, U.S. Ser. No. 62/437,983, filed on Dec. 22,2016, and U.S. Ser. No. 62/462,655, filed on Feb. 23, 2017, all of whichare incorporated in their entireties by reference herein.

BACKGROUND

This disclosure relates to placental tissue and methods of repairing,reconstructing, or regenerating musculoskeletal degenerative processesor injuries in a patient.

SUMMARY

An embodiment includes a method of treating musculoskeletal tissueinjury or degeneration in a subject. A method can comprise threading atleast one placental tissue streamer through a midsubstance of a tissue,to form a tissue hybrid; and attaching or anchoring the placental tissuestreamer to a subject at a placental tissue streamer attachment site.The threaded placental tissue streamer can be surrounded by the tissue.The threading of the placental tissue streamer through the midsubstanceof the tissue can take place either pre-repair or pre-augmentation. Thethreading of the placental tissue streamer through the midsubstance ofthe tissue can take place either post-repair or post-augmentation. Twoor more placental tissue streamers can be grouped together intoplacental tissue streamer ropes or placental tissue streamer stacks. Theplacental tissue stacks or placental tissue ropes can be threadedthrough the midsubstance of the tissue.

An embodiment includes a method of treating musculoskeletal tissueinjury or degeneration. The method can comprise contacting one or moreplacental tissue streamer ropes or placental tissue streamer stacks witha tissue to be treated, and optionally attaching the one or moreplacental tissue streamer ropes or placental tissue streamer stacks tothe tissue to be treated or to healthy tissue adjacent to the tissue tobe treated.

An embodiment includes a tissue hybrid comprising a tissue midsubstance;and at least one placental tissue streamer, wherein the placental tissuestreamer is located through the midsubstance of the tissue hybrid. Thetissue can comprise allograft tissue, autograft tissue, xenografttissue, engineered tissue scaffold, or combinations thereof. Two or moreplacental tissue streamers can be entwined or stacked and locatedthrough the midsubstance of the tissue.

An embodiment includes a method of treating musculoskeletal tissueinjury or degeneration in a subject. The method can comprise contactingan engineered scaffold placental tissue steamer hybrid with a tissue tobe treated, and optionally attaching the engineered scaffold placentaltissue steamer hybrid to the tissue to be treated or to healthy tissueadjacent to the tissue to be treated,

An embodiment includes a method of treating musculoskeletal tissueinjury or degeneration in a subject. The method can comprise wrapping atleast one placental tissue streamer, amnion tissue streamer, placentaltissue patch hybrid, or engineered scaffold placental tissue streamerhybrid around a tissue, engineered tissue scaffold, or graft, to form atissue hybrid, and contacting the tissue hybrid to a tissue to betreated. The tissue hybrid can be attached to the tissue to be treatedor to healthy tissue adjacent to the tissue to be treated. The tissuehybrid can be contacted with one or more biological agents prior tocontacting the tissue hybrid with the tissue to be treated. Theplacental tissue streamer, amnion tissue streamer, placental tissuepatch hybrid, or engineered scaffold placental tissue streamer hybridcan be wrapped around the tissue such that one or more compartments areformed between the tissue and the placental tissue streamer, placentaltissue patch hybrid, or engineered scaffold placental tissue streamerhybrid, and wherein one or more biological agents are placed within theone or more compartments. The engineered scaffold placental tissuestreamer hybrid can comprise one or more compartments that contain oneor more biological agents or that can be filled with one or morebiological agents.

An embodiment includes a placental tissue steamer suture hybrid,comprising a suture with an inner hollow bore and at least one placentaltissue streamer, wherein the placental tissue streamer is located withinthe inner hollow bore of the suture. The suture can have pores or gaps.

An embodiment includes a method of treating a musculoskeletal tissueinjury or degeneration. The method can comprise threading at least oneplacental tissue streamer through a suture, yielding a placental tissuestreamer suture hybrid, and attaching or contacting the placental tissuestreamer suture hybrid to a tissue to be treated or to healthy tissueadjacent to the tissue to be treated. Alternatively, the placentaltissue streamer suture hybrid can be passed through a suture anchor toform a placental tissue streamer suture hybrid anchor. The placentaltissue streamer suture hybrid anchor can be attached or contacted to atissue to be treated or to healthy tissue adjacent to the tissue to betreated.

An embodiment includes a placental tissue patch hybrid comprisingplacental tissue and a mesh construct, wherein the placental tissue isinterwoven into the mesh construct, present in a compartment of the meshconstruct, attached on the top, attached to the bottom, or attached toboth the top and bottom of the mesh construct.

An embodiment includes a method of treating a musculoskeletal tissueinjury or degeneration. The method can comprise attaching or contactinga suture placental tissue hybrid or a placental tissue patch hybrid to atissue to be treated or to healthy tissue adjacent to the tissue to betreated.

In an embodiment musculoskeletal injury or degeneration can be aconnective tissue injury or degeneration, cartilaginous tissue injury ordegeneration, fibrous tissue injury or degeneration, muscle tissueinjury or degeneration, or skeletal tissue injury or degeneration. Themusculoskeletal injury or degeneration can be to tendon, cartilage,ligament, connective tissue, muscle, joint, intervertebral disk, orbone. The tissue can be allograft, autograft, xenograft, engineeredtissue scaffold, or combinations thereof.

The placental tissue or placental tissue streamer can comprise amniotictissue; chorionic tissue; umbilical cord tissue; viable tissue cellsnative to amniotic tissue, viable tissue cells native chorionic tissue;viable tissue cells native umbilical cord tissue; extracellular matrixthat is native to the amniotic tissue; decellularized placental tissue;decellularized amnion, extracellular matrix that is native chorionictissue; extracellular matrix that is native umbilical cord tissue;hypothermic amniotic tissue, hypothermic chorionic tissue; hypothermicumbilical cord tissue; cryopreserved amniotic tissue; cryopreservedchorionic tissue; cryopreserved umbilical cord tissue; chemicallypreserved amniotic tissue; chemically preserved chorionic tissue;chemically preserved umbilical cord tissue; normothermic perseveredamniotic tissue; noromothermic chorionic tissue; normothermic umbilicalcord tissue; dehydrated, desiccated, or lyophilized amniotic tissue;dehydrated, desiccated, or lyophilized chorionic tissue; dehydrated,desiccated, or lyophilized umbilical cord tissue, or combinationsthereof.

An embodiment can comprise a kit comprising one or more of a sutureplacental tissue hybrid, an engineered scaffold placental tissue hybrid,and a placental tissue patch hybrid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Cross-section of a tissue hybrid reconstruction showingplacental tissue streamers in the midsubstance of the grafted ACL(collagen fibers) or muscle (muscle fibers). A placental tissue streamercan also be present in the midsubstance of meniscus, intervertebral diskmaterial, tendons, grafts, etc.

FIG. 2. Anterior view of knee with a placental tissue hybrid 1 connectedat tissue attachment site 2 in the femur 3 and at a tissue attachmentsite 2 in the tibia 4.

FIG. 3. Representation of how multiple placental tissue streamers(placental tissue streamer one 5, placental tissue streamer two 6, andplacental tissue streamer three 7) are entwined to become a placentaltissue streamer rope.

FIG. 4. Cross-section (left) and longitudinal representation (right) ofan embodiment where the placental tissue streamer 8 is surrounded by asuture 9. The lines of the placental streamer in the longitudinalrepresentation are dashed to show that the placental streamer is locatedinside of the suture's tubular sheath defining an empty bore.

FIG. 5A (top) and FIG. 5B (bottom) view of a mesh construct patch havingtwo compartments 10 capable of containing biologics.

FIG. 6 shows an anterior cruciate ligament (ACL) prepared graftpreparation, which is a bone block 11 to soft tissue 12 (e.g., tendon)graft. A graft can also be a soft tissue to a soft tissue graft.

FIG. 7 shows the initial fixation sutures 13 of a collagen membrane 14representing, for example, placental tissue to a graft.

FIG. 8 shows the initial fixation sutures 13 and an initial fixationstitch 15 of a collagen membrane 14 representing, for example, placentaltissue to a graft.

FIG. 9 shows a graft wrapped with a membrane 16 representing, e.g.,placental tissue.

FIG. 10 shows a membrane representing, e.g., placental tissue wrappedaround a graft with sutures.

FIG. 11 shows a membrane representing a placental tissue wrapped arounda graft with cerclage sutures 17 and a running suture 18.

FIG. 12 shows an amnion membrane wrapped graft positioned into a knee(arthroscopic view).

FIG. 13 shows injection of an amnion wrapped graft with a biologic agentafter fluid is removed (arthroscopic view).

FIG. 14 shows injection of an amnion wrapped graft with a biologic agentafter fluid is removed (arthroscopic view).

FIG. 15 shows an amnion streamer being placed anterior to posterior tofill the gap of an articulated tear of the tendon of the supraspinatus.

FIG. 16 shows a SutureBridge™ tissue repair 20 of soft tissue andincludes an amnion streamer 19 running through the soft tissue.

DETAILED DESCRIPTION

Placental tissue can be used in the augmentation of repair,reconstruction, and regeneration of patient musculoskeletal tissueinjury due to the natural components of the placental tissue as well asthe lack of antigens.

Placental tissue can be used for the treatment of musculoskeletal tissueinjuries and degenerative conditions in a patient. Tissues that can betreated, repaired, regenerated, and/or restored include, for example,ligaments, joints, connective tissue, cartilage, intervertebral disk,bone, anterior cruciate ligament, posterior cruciate ligament, medialcollateral ligament, lateral collateral ligament, popliteofibularligament, posterolateral corner, patellar tendon, quadriceps tendon,medial or lateral meniscus, medial or lateral patellofemoral ligament,anterolateral ligament, rotator cuff tendon, glenoid labrum,subscapularis tendon, biceps tendon, coracoclavicular ligaments,anterior talofibular ligament, calcaneofibular ligament, springligament, posterior tibialis, anterior tibialis, tendon grafts, extensorand flexor tendons of the hand, foot, upper and lower extremities,intervertebral disk material, damaged or torn muscle tissue includingbut not limited to, the hamstring muscles, quadriceps, gastrocnemius,soleus, adductors, abductors, hip external and internal rotators,flexors, wrist, elbow and hand extensors, flexors, and other tendons andmuscles throughout the musculoskeletal system. A musculoskeletal tissueinjury or degeneration can be, for example, a connective tissue injuryor degeneration, cartilaginous tissue injury or degeneration, fibroustissue injury or degeneration, muscle tissue injury or degeneration, orskeletal tissue injury or degeneration.

Placental tissue, optionally in conjunction with mesh constructs orsutures, can be incorporated into a primary tissue repair, allograftreconstruction, autograft reconstruction, engineered tissue scaffoldreconstruction, or in regenerative applications thereby producing atissue hybrid. A tissue hybrid can provide a bio-inductive scaffold foruse in tissue repair (tendinopathies of the shoulder, knee, elbow, andankle, for example). In reconstruction procedures, the vascularity of atissue may be compromised, particularly in a tissue's inner-substance(e.g., an ACL reconstruction). A tissue hybrid or placental tissue, asdescribed herein, can augment healing, incorporation, or regeneration ofa damaged tissue over a non-hybrid primary tissue repair orallograft/autograft or engineered tissue scaffold.

Placental tissue (e.g., tissue hybrid, placental tissue streamer,placental tissue patch hybrid, suture placental tissue hybrid,engineered scaffold placental tissue hybrid) can be incorporated into aninjured or degenerative tissue for the augmentation of healing thedamaged tissue, where the damage to the tissue is not severe enough towarrant structural surgical repair. Examples of such tissue damage notrequiring formal surgical structural repair including, for example,rotator cuff tendinopathy, partial thickness tear of tissue, patellartendinitis, lateral epicondylitis, medial meniscal degeneration,degenerative disk disease, or the like.

In an embodiment, degenerative tissues that are not necessarily in needof structural repair are treated. For example, rotator cuff tendinosis,rotator cuff partial thickness tears, degenerative meniscal tears,Achilles tendinopathy, lateral epicondylitis, patellar tendinopathy, anddegenerative disk disease can be treated by injecting and/or insertingor augmenting the midsubstance with a placental streamer to augmenthealing without the need for a formal structural surgical repair.Degenerative tissues can also be treated by contacting or wrapping thesuture placental tissue hybrids, engineered scaffold placental tissuehybrid, or placental tissue patch hybrids with or around the degeneratedtissues. See, e.g., FIG. 15.

Degenerative tissue may be partially torn but not structurallycompromised. The placement of placental tissue streamers, tissuehybrids, placental tissue patch hybrids, and suture placental tissuehybrids in this case is intended to augment healing, repair, and/orregeneration of the damaged or degenerative tissue. Examples of thisapplication include but are not limited to, tendinosis, partialthickness tendon tears, degenerative disk disease or annular tears,degenerative meniscal tears, degenerative labral tears, partialthickness ligament tears, muscle injury, ligament sprains, andatrophic/fatty infiltrated muscle such as rotator cuff muscle damagedwith Goutallier stages 1-4 muscle atrophy/fatty infiltration.

Tissue Hybrids

In embodiments of the present disclosure, a tissue hybrid is created bythreading a placental tissue streamer through a midsubstance of a tissueor engineered tissue scaffold, placing a placental tissue streamer alongthe tissue or engineered tissue scaffold, or wrapping the tissue orengineered tissue scaffold with a placental tissue streamer. Othertissue hybrids include placental tissue hybrids, engineered tissueplacental tissue hybrids, suture placental tissue hybrids, and placentaltissue patch hybrids, which can be threaded through a midsubstance of atissue or engineered tissue scaffold, placed alongside a tissue orengineered tissue scaffold, anchored or attached to a tissue orengineered tissue scaffold, or wrapped around a tissue or engineeredtissue scaffold. In an embodiment, the tissue is healthy tissue. In anembodiment, the tissue is damaged or degenerated tissue. In anembodiment, the tissue is healthy graft tissue or an engineered tissuescaffold. The midsubstance of the tissue refers to the longitudinalinside of the tissue or engineered tissue scaffold.

A tissue of a tissue hybrid can be autograft, allograft, xenograft,engineered tissue scaffold, or combinations of the like. Xenograftmaterials can be obtained from mammalian sources, including, but notlimited to, equine, canine, feline, bovine, porcine, sheep, or goat, andhuman sources.

Placement

In an embodiment, at least one placental tissue streamer is threadedthrough a damaged tissue or engineered tissue scaffold, creating atissue hybrid. In an embodiment, a tissue hybrid comprises one or moreamniotic membrane streamers and a damaged tissue, where the streamer islocated in the midsubstance of the damaged tissue or within the damagedtissue. In an embodiment one or more placental tissue streamers(including placental tissue streamer ropes and placental tissue streamerstacks) are placed alongside or in contact with the tissue to betreated. In this case, the one or more placental streamers canoptionally be attached to the tissue to be treated via, for example, oneor more sutures. In an embodiment, the tissue of the tissue hybrid isdamaged tissue. In an embodiment, the tissue of the tissue hybrid ishealthy tissue. In an embodiment, the midsubstance comprises a midpoint,which refers to the intermediate or longitudinally central part of thetissue. The midsubstance does not have to be the exact center of thetissue. In an embodiment, a placental tissue streamer can be run throughthe midsubstance, adjacent to the midpoint of the tissue. The streamercan be threaded through the tissue so as to run along the length of thetissue. In another embodiment, at least one streamer is threaded througha tissue graft (e.g., an allograft, autograft, or xenograft) orengineered tissue scaffold that will be used to repair reconstruct orregenerate the injured soft tissue of the patient. In this embodiment,the tissue hybrid comprises a placental tissue streamer and a healthytissue graft, allograft, autograft, or xenograft, where the streamer isthreaded through the midsubstance of the tissue graft. A placentaltissue streamer can also be placed alongside, on the top of, on thebottom of, or wrapped around a tissue (healthy, damaged, degenerated, orgraft tissue) or engineered tissue scaffold.

Streamer and Streamer Placement

A placental tissue streamer can be attached to damaged, injured tissue,degenerated tissue, or healthy graft tissue of a tissue hybrid or to aplacental tissue streamer attachment site. A placental tissue streamercan also be attached to an engineered tissue scaffold. When a streameris attached to a placental tissue streamer attachment site, the streameris located within healthy tissue of the patient in the proximity of theinjury or damage. A streamer attachment site can be located in muscle,tendon, ligament, joint, connective tissue, cartilage, bone,intervertebral disk, or the like. A placental tissue streamer attachmentsite can be located in the tissue hybrid. In an embodiment, theplacental tissue streamer comprises two ends, where one end of theplacental tissue streamer can be attached to a placental tissue streamerattachment site; the second end of the placental tissue streamer can beattached to a different placental tissue streamer attachment site. Theplacental tissue streamer can be attached at a placental tissue streamerattachment site through attachment processes known in the art. Anexample of such an attachment process is suturing the end of a streamerto the tissue of the tissue hybrid, where the tissue of the tissuehybrid is damaged or injured tissue, healthy graft tissue, an engineeredtissue scaffold, or combinations thereof. In an embodiment, a streameris not attached to damaged or injured tissue, healthy graft tissue, orengineered tissue scaffold; rather, the ends of the streamer and thetissue hybrid are attached independently to the same two healthy tissueattachment sites. In such an embodiment, the healthy tissue attachmentsite can be located in non-damaged tissue of the patient in proximity tothe injury, damaged tissue, or wound. The non-damaged tissue can bemuscle, tendon, ligament, connective tissue, joint, cartilage, bone,intervertebral disk, or the like. For example, in an anterior cruciateligament repair or reconstruction, one end of the patellar tendon can beattached to the femur while the other end is attached to the tibia. Inthis example, the tissue hybrid, along with the streamer located throughthe midsubstance of the tissue hybrid can be attached to the bone at thefemur and tibia. In such an example, there are two healthy tissueattachment sites, at each end of the patellar tendon graft. Attachingboth the streamer and the tissue hybrid at the same attachment siteallows for anchoring of both the streamer and the tissue hybrid. Such anattachment is performed by methods known in the art.

In an embodiment, a streamer is threaded through the tissue while thetissue is still attached to the patient at the tissue's naturalattachment site. A tissue's natural attachment site is the locationwhere that tissue, if healthy, would be attached to the subject's body.For example, an Achilles tendon that is ruptured between the tissue'snatural attachment sites at the calcaneus and gastrocnemius is stillattached at its natural attachment sites. The streamer is threadedthrough the midsubstance of the tissue starting near the tissue'snatural attachment site. The streamer is attached to the Achilles tendonthrough known methods, such as suturing or at the bony insertion throughthe use of a suture anchor. The streamer runs the length of the Achillestendon and is attached to the tendon at streamer attachment points nearwhere the Achilles tendon is attached to the calcaneus andgastrocnemius.

In an embodiment one or more placental tissue streamer ropes orplacental tissue streamer stacks are contacted with a damaged tissue(e.g., placing the ropes or stacks alongside the damaged tissue). Theone or more placental tissue streamer ropes or placental tissue streamerstacks can optionally be attached to the damaged tissue via, for examplesutures.

Rotator Cuff

In an embodiment, rotator cuff tendinopathy can be treated with theinsertion of an amniotic streamer. Rotator cuff tendinopathy is oftennot treated initially through surgical means; rather it is usuallytreated through subacromial steroid injection. However, in the exemplaryembodiment, a streamer is inserted into the damaged rotator cuff tissue.This can be done through known surgical means, but also throughultrasound guided injection/insertion. The surgeon can use a needleloaded with a streamer and an ultrasound to guide the needle to theproper location. Then the streamer can be injected/inserted into thetissue.

Placental tissue streamers can also be delivered to other tendinopathiesin the patellar tendon, lateral and medial epicondylitis, ankle,Achilles, and to muscle strains and tears such as the hamstring orquadriceps muscles, gastrocnemius muscle, soleus muscle, or other muscleinjury or degeneration, as well as sprained ligaments such as around theankle, knee, elbow, or shoulder.

Anterior Cruciate Ligament (ACL)

In an embodiment, an ACL is treated. A tissue graft, as known in theart, can be used to replace the damaged ACL. The tissue graft can eitherbe a patellar tendon of the patient, the patellar tendon of a cadaver, ahamstring graft of the patient, or a hamstring graft of a cadaver,quadriceps tendon of the patient or cadaver, or other tendon such as thetibialis anterior or posterior of a cadaver. At least one placentaltissue streamer can be threaded through the midsubstance of the tissuegraft. Once the streamer is threaded through the midsubstance of thetissue graft, the tissue hybrid is formed as shown in FIG. 1. The tissuehybrid is then placed in the patient, as shown in FIG. 2.

In an embodiment, an ACL can be repaired or reconstructed using a tissuegraft. The graft is obtained by methods known in the art. A placentaltissue streamer can be threaded through the midsubstance of the tissuegraft for the length of the tissue graft, forming a tissue hybrid. Theplacental tissue streamer can be sutured to the tissue graft at each endof the tissue graft. The tissue hybrid can then be administered to thepatient and attached at an anchoring site, a site of attachment, locatedin the subject's femur and an anchoring site in the subject's tibia.

A full tear of a subject's ACL can be repaired or reconstructed withmethods described herein. A tissue graft can be used to replace the tornACL where the tissue graft comprises a midsubstance, a first end, and asecond end. A placental tissue streamer can be threaded through themidsubstance of the tissue graft creating a tissue hybrid. The first endof the tissue hybrid can be attached to the subject at an anchoring siteon the subject's femur. The second end of the tissue hybrid can beattached to the subject at an anchoring site on the subject's tibia.

One exemplary method is the repair of a human anterior cruciateligament. A placental tissue streamer can be removed from the site ofstorage and thawed if the streamer was cryopreserved. The patellartendon of the patient can be removed through methods known in the art.The amniotic tissue streamer can be threaded through the central portionof the patellar tendon. Once the streamer is threaded through themidsubstance of the patellar tendon, the tissue hybrid is formed. Thestreamer is not attached to the tissue hybrid. Rather, the tissue hybridcan be placed in the subject and is attached to the two healthy tissueattachment sites, one in the femur and one in the tibia.

Achilles Tendon

In an embodiment, a fully or partially ruptured human Achilles tendoncan be repaired. A placental streamer is threaded through themidsubstance of the Achilles tendon starting at the calcaneus end of thetendon. The streamer can be attached to the Achilles tendon near thesite of where the Achilles tendon is attached to the calcaneus. Thestreamer continues to be threaded through the midsubstance for thelength of the Achilles tendon until reaching the gastrocnemius. Thestreamer can then be attached to the Achilles tendon near the site ofwhere the Achilles tendon and the gastrocnemius attach to each other.Where the tendon is avulsed off of the bone, the streamer can be used toattach the damaged tissue to the bone by direct bone attachment via asuture anchor where the placental streamer is either threaded throughthe anchor eyelet, or placed within a hollow suture that is threadedthrough the suture anchor eyelet.

For example, an Achilles tendon can comprise a midsubstance, acalcaneous end, and/or a gastrocnemius end where the calcaneous endattaches to the subject's calcaneous, and/or the gastrocnemius endattaches to the subject's gastrocnemius. The subject's damaged Achillestendon can be the tissue of the tissue hybrid. The placental tissuestreamer comprises two ends: a first end and a second end and isthreaded through the midsubstance of the damaged Achilles tendon,wherein the first end of the placental tissue streamer is inserted ateither the calcaneous end or the gastrocnemius end of the Achillestendon, and the placental tissue streamer is threaded to the oppositeend of the Achilles tendon. One of the two placental tissue streamerends is attached to an attachment site at the calcaneous end of theAchilles tendon; and the other placental tissue streamer end is attachedto an attachment site at the gastrocnemius end of the Achilles tendon.

In an embodiment, a damaged Achilles tendon can be strengthened usingmultiple placental tissue streamers. The Achilles tendon can be repairedor augmented by methods known in the art or with the use of anaugmentative engineered tissue scaffold containing placental tissuestreamers. After the repair or augmentation, two or more placentaltissue streamers are entwined to form a placental tissue streamer rope,as shown in FIG. 3. The rope can be threaded through the midsubstance ofthe Achilles tendon starting at the calcaneus end of the tendon. Therope can be sutured to the Achilles tendon near the site of where theAchilles tendon is attached to the calcaneus. The rope continues to bethreaded through the midsubstance for the length of the Achilles tendonuntil reaching the gastrocnemius. The rope can then be sutured to theAchilles tendon near the site of where the Achilles tendon and thegastrocnemius attach to each other.

Midsubstance Threading

In an embodiment, a placental tissue streamer is threaded through themidsubstance of a tissue post-repair, where the injury is repairedbefore the streamer is threaded through the tissue. For example, in atendon rupture, the tendon can be sutured together at the rupture site.Then a placental tissue streamer threaded through the midsubstance ofthe repaired tendon and attached to both ends of the tendon near thetendon's natural attachment site.

In an embodiment, a placental tissue streamer is threaded through themidsubstance of a tissue; however, the streamer is not completelycovered by the tissue. In such an embodiment, the streamer exits themidsubstance and outer layer of the tissue, becoming exposed to theenvironment in the patient cavity.

In an embodiment, a placental tissue streamer is located adjacent to therepaired tissue. In such an embodiment, one end of the streamer isattached at a placental tissue streamer attachment site and the otherend of the streamer is attached at a second placental tissue streamerattachment site in such a way that the streamer spans the tissue at thesite of repair.

Wrapping

A graft (e.g., allograft, autograft, xenograft, engineered tissuescaffold) or tissue (e.g., a tissue to be treated) can be wrapped withone or more placental tissue streamers, engineered scaffold placentaltissue hybrids, suture placental tissue hybrids, collagen membrane, orplacental tissue patch hybrids. The placental tissue streamers,engineered scaffold placental tissue hybrids, suture placental tissuehybrids, collagen membrane, or placental tissue patch hybrids can be,for example, anchored to themselves, to the graft, to the tissue to betreated, to tissue adjacent or surrounding the tissue to be treated, orto one or more attachment sites. A placental tissue streamer, engineeredscaffold placental tissue hybrid, suture placental tissue hybrid,collagen membrane, or placental tissue patch hybrid can be wrappedaround a graft or tissue such that the graft or tissue is substantiallycovered by the streamer or hybrid. In an embodiment, 50, 60, 70, 80, 90,95, 98, 99 or 100% (or any range between about 50% and 100%) of thesurface of the graft or tissue is covered by the wrapped placentaltissue streamer or hybrid. In an embodiment, all of the graft or tissueis covered by the wrapped placental tissue streamer, engineered scaffoldplacental tissue hybrid, suture placental tissue hybrid, collagenmembrane, or placental tissue patch hybrid except for the ends of thegraft or tissue. In an embodiment the placental tissue steamer,engineered scaffold placental tissue hybrid, suture placental tissuehybrid, or placental tissue patch hybrid is of a width that issufficient for the desired coverage of the graft or tissue and iswrapped one or more times around the graft or tissue. In an embodiment,the placental tissue steamer, engineered scaffold placental tissuehybrid, suture placental tissue hybrid, collagen membrane, or placentaltissue patch hybrid is not as wide as the length of the graft or tissueand is wrapped around the graft or tissue so that that longitudinaledges (long edges) of the placental tissue steamer, engineered scaffoldplacental tissue hybrid, suture placental tissue hybrid, collagenmembrane, or placental tissue patch hybrid overlap to confer fullcoverage of the graft or tissue. The latitudinal edges (short edges) ofthe placental tissue steamer, engineered scaffold placental tissuehybrid, suture placental tissue hybrid, collagen membrane, or placentaltissue patch hybrid can be anchored either to the graft or tissue itselfor to one or more attachment sites.

Prior to wrapping the graft or tissue with one or more the placentaltissue steamers, engineered scaffold placental tissue hybrids, sutureplacental tissue hybrids, collagen membranes, or placental tissue patchhybrids, the graft or tissue can be contacted with one or morebiological agents, such as platelet rich plasma (PRP), bone marrowconcentrate (BMC), adipose derived growth factors, viscous amnion,amniotic epithelial cells (AE) cells, stem cells, growth factors (e.g.,epidermal growth factor (EGF), platelet-derived growth factor (PDGF),vascular endothelial growth factor (VEGF), angiogenin, transforminggrowth factor-β2 (TGF-β2), and tissue inhibitors of metalloproteinases(e.g., TIMP-1 and TIMP-2)), adipose derived growth factors, umbilicalcord-derived cells (UCD) cells, chorionic trophoblasts (CT), amnionderived or chorion derived mesenchymal stromal cells, or combinationsthereof. Biological agents are any agents that provide enhanced healing,regeneration, and improved graft incorporation. One or more of thebiological agents (e.g., PRP or BMC) can be obtained from the patient tobe treated.

In an embodiment, a placental tissue steamer, engineered scaffoldplacental tissue hybrid, suture placental tissue hybrid, or placentaltissue patch hybrid is wrapped around the tissue or graft such that oneor more pockets or spaces are created between the tissue or graft andthe placental tissue streamer or hybrid. One or more biological agentscan be injected or otherwise provided to the one or more pockets orspaces.

In one embodiment, at the completion of ACL graft preparation (FIG. 6),a graft can be wrapped in placental tissue (e.g., amnion, chorion, orumbilical cord) or a placental tissue streamer hybrid or collagenmembrane (FIG. 7-11). One, two, or more sutures can connect the graft tothe placental tissue or placental tissue streamer hybrid wrap at eitherend (FIGS. 7 and 8) or at one end of the graft. The graft can be wrappedmultiple times creating multiple layers (FIG. 9). One cerclage stitchcan be placed at either end of the placental tissue or placental tissuestreamer hybrid wrap after wrapping. (FIG. 10). A running stitch canalso be placed at the end of the wrap (FIG. 11). The two cerclagestitches and the running stitch can create multiple water-tightcompartments (i.e., pockets or spaces) dependent on the number of layersof wrap. The compartments, which can be water-tight, can be filled orcontacted with a biological agent after implantation. (FIG. 12-14). Inan embodiment, the biological agent comprises stem cells that can beinjected into a water-tight compartment. In an embodiment, the stemcells are harvested from the patient receiving the ACL graft. The stemcells can be harvested from the distal femur (the same surgical siteused for the ACL graft) using a bone marrow aspiration needle and stemcells can be concentrated or purified from the bone marrow aspirate.

Once the graft has been inserted into the joint and secured (FIG. 12),the arthroscopic fluid can be evacuated from the joint. The water-tightcompartments of the placental tissue streamer wrapped graft can beinjected with a biological agent (e.g., platelet rich plasma (PRP); bonemarrow concentrate (BMC); viscous amnion; growth factors; stem cells(e.g., AE stem cells), etc.) (FIG. 13-14).

An embodiment includes a method of treating musculoskeletal tissueinjury or degeneration in a subject. At least one placental tissuestreamer, placental tissue patch hybrid, or engineered scaffoldplacental tissue streamer hybrid is wrapped around a tissue (e.g.,damaged, injured, or degenerated tissue, an engineered scaffold, orgraft), to form a tissue hybrid. The tissue hybrid is contacted with amusculoskeletal tissue injury or degeneration site in a subject (e.g. asite of damaged, injured, or degenerated tissue) or tissue to betreated. The placental tissue streamer, placental patch hybrid, orengineered scaffold placental tissue streamer hybrid or tissue hybridcan be optionally attached to the subject at, for example, the damaged,injured, or degenerated tissue (i.e., the tissue to be treated) or tohealthy tissue adjacent to or surrounding the damaged, injured, ordegenerated tissue.

Placental Tissue

Placental tissue contains immunosuppressive cytokines and lacks surfaceantigens, the combination of which results in a lack of rejection inpatients treated with placental tissue. Immunosuppressive cytokinesinclude, but are not limited to, interleukin-4, interleukin-10, andtransforming growth factor. Antigens important for the lack of rejectioninclude, but are not limited to, HLA-A, HLA-B, HLA-C, andβ2-microglobulin.

Placental tissue can be collected from a female mammal at the time thefemale mammal is giving birth to offspring. Placentae are usuallydiscarded following child birth. Placental tissue can be collectedinstead of discarding the entire placenta to medical waste. Thiscollection can take place from a cesarean birth. In an embodiment,collected placental tissue is prepared by removing epithelial cells bygentle mechanical scraping or by other well-known methods. In anotherembodiment, epithelial cells are not removed from the collectedplacental tissue.

In an embodiment, placental tissue is biopreserved, meaning the tissueis recovered and prepared so that the integrity and functionality ofcells and tissues are able to be held outside their native environmentfor extended storage times. Biopreservation methods are well known, andsuch methods are used in the preparation of placental tissue. Suchmethods include, but are not limited to, hypothermic preservation,chemical preservation, dehydration, lyophilizaton, desiccation, andcryopreservation. Hypothermic preservation is the storage of tissue atlower than room or body temperature but without freezing the tissue.Cryopreservation is the preservation of tissue by freezing the tissueand storing at temperatures lower than 0° C. The placental tissue canalso be stored through normothermic culture, where the tissue is kept atthe temperature of its native environment. As is known in the art, themedium that the tissue is stored in depends upon the method ofbiopreservation used.

In embodiments where placental tissue is biopreserved, the tissue isreconstituted prior to methods disclosed herein. Biopreserved placentaltissue can be reconstituted in a solution such as saline. The solutioncan comprise a) platelet rich plasma (PRP), b) bone marrow concentrate(BMC), c) growth factors, d) stem cells, e) adipose derived growthfactors, f) amniotic epithelial cells (AE) cells, g) umbilicalcord-derived cells (UCD) cells, h) chorionic trophoblasts (CT), i)amnion derived or chorion derived mesenchymal stromal cells, j) chemicaladditives, or h) combinations thereof. In an embodiment, growth factorsinclude epidermal growth factor (EGF), platelet-derived growth factor(PDGF), vascular endothelial growth factor (VEGF), angiogenin,transforming growth factor-β2 (TGF-β2), and tissue inhibitors ofmetalloproteinases (e.g., TIMP-1 and TIMP-2). One or more of thebiological agents (e.g., PRP or BMC) can be obtained from the patient tobe treated.

AE cells as mentioned above can have at least one cell surface markerselected from the group consisting of stage-specific embryonic antigen-3(SSEA-3), SSEA-4, tumor rejection antigen 1-60 (TRA1-60), and TRA1-81.Similarly, AE cells may have at least one molecular marker selected fromthe group consisting of octomer-4 (OCT-4), NANOG, sex determining regionY-box 2 (SOX-2), Lefty-A, fibroblast growth factor-4 (FGF-4), REX-1, andteratocarcinoma-derived growth factor 1 (TDGF-1).

In an embodiment, AE cells can be also be administered to a repair orreconstruction in a patient. In an embodiment, a solution comprising AEcells can be administered to a tissue graft, tissue hybrid, or placentalstreamer ex vivo prior to implantation into a subject. Although AE cellscan comprise multipotent cells, the administration of AE cells inclinical settings and to immunodeficient mice (e.g., SCID and Rag-2knockout mice) have not produced teratomatous growth.

In an embodiment, a method includes preparing PRP and/or BMC from apatient, reconstituting a placental tissue (e.g., amnion or chorion)with the prepared PRP and/or BMC, and augmenting the patient's damagedsoft tissue or graft with the placental tissue. In an embodiment, amethod includes reconstituting a placental tissue with media comprisingAE cells, and augmenting a patient's damaged soft tissue or graft withthe placental tissue. In an embodiment, a method includes preparing PRPand/or BMC from a patient; reconstituting placental tissue with the PRPand/or BMC from the patient supplemented with AE cells; and augmentingthe patient's damaged soft tissue or graft with the placental tissue.Additionally, a placental tissue streamer or placental tissue hybrid canbe injected or attached to the damaged soft tissue or graft'smidsubstance in any of the disclosed methods herein.

In an embodiment, placental tissue (e.g., amnion, chorion, or umbilicalcord tissue) is decellularized. Tissues can be decellularized using anymethod of decellularization known in the art. For example, amnion can bedecellularized by removing the cell membrane and cellular debris usinggentle mechanical disruption methods. These methods disrupt the cellularmembrane, while avoiding damaging or disturbing the amnion's complexinfra-structure. Gentle mechanical disruption methods include, forexample, scraping the surface of the amnion, agitating the amnion, orstirring and washing the amnion in a suitable volume of fluid, e.g.,distilled water or saline (e.g., 0.9% saline), for a suitable amount oftime (e.g., about 15, 30, 60 , 90 minutes or more). The amnion isthereby disrupted and the cellular debris is removed from the amnion. Inanother embodiment, the amnion, chorion, umbilical cord tissue orplacental tissue is not decellularized.

A placental tissue (e.g., a placental streamer) can comprise viabletissue cells native to placental tissue (e.g., amniotic tissue,chorionic tissue, umbilical cord tissue, or combinations thereof),extracellular matrix that is native to placenta (e.g., amniotic tissue,chorionic tissue, umbilical cord tissue, or combinations thereof), orboth viable tissue cells native to placental tissue and extracellularmatrix that is native to placental tissue. A placental tissue can beamnion or an amnion streamer. Likewise, placental tissue according theembodiments disclosed herein can also comprise non-viable cells.

Engineered Tissue Scaffolds

In an embodiment, an engineered tissue scaffold comprises a structuralcomponent and cells attached to the engineered tissue scaffold. In anembodiment, an engineered tissue scaffold is a fully developed tissuethat comprises a collection of cells assembled to fulfill a commonfunction. In an embodiment, an engineered tissue scaffold is used inplace of a damaged tissue or tissue graft. In an embodiment, anengineered tissue scaffold is used in conjunction with damaged tissue ortissue graft. In an embodiment, an engineered tissue scaffold, damagedtissue, and tissue graft are used in combination. In an embodiment, anengineered tissue scaffold comprises a midsubstance of a tissue where atleast one placental tissue streamer is located.

Engineered tissue scaffolds are materials that can be used to encouragedesirable cellular interactions and the formation of new functionaltissues. One of more types of cells can be ‘seeded’ into or ontoscaffolds. Cells include, for example, bone marrow mesenchymal stemcells (BM-MSCs), umbilical cord-derived mesenchymal stem cells(UC-MSCs), adult or embryonic stem and progenitor cells, inducedpluripotent cells, tenocytes, osteoblasts, nerve cells, cardiac cells,myocytes, fibroblasts or combinations thereof.

Engineered tissue scaffolds can be made up of natural or syntheticmaterials that can be biodegradable or permanent). Examples of thesematerials used in engineered tissue scaffolds are polyesters, nylon,polyurethrine, polylactic acid (PLA), polyglycolic acid (PGA),polycaprolactone (PCL), polystyrene, poly-I-lactic acid (PLLA),poly-dl-lactic-co-glycolic acid (PLGA), polyvinyl acetate (PVA),polyvinyl chloride (PVC), polyethylene glycol (PEG), hydrogels,hydrogels comprising PLA, PGA, PCL, polystyrene, PLLLA, PLGA, PVA, PVC,PEG, or combinations thereof, agarose, alginate, hyaluronan, proteins(e.g., silk, collagen, gelatin, fibrinogen, fibrin, elastin, keratin,actin, and myosin), polysaccharidic materials (e.g., cellulose, amylose,dextran, chitin, chitosan and glycosaminoglycans (GAGs), orpolynucleotides (DNA, RNA).

In an embodiment an engineered tissue scaffold comprises one or moreplacental tissue streamers. The combination of an engineered tissuescaffold and one or more placental tissue streamers is an engineeredscaffold placental tissue hybrid. The one or more placental tissuestreamers can be attached to (by, for example sutures or anchors) orwoven into an engineered tissue scaffold to form an engineered scaffoldplacental tissue hybrid. Optionally, the one or more placental tissuestreamers can be held in contact with an engineered tissue scaffoldwithout sutures or anchors to form an engineered scaffold placentaltissue hybrid.

An engineered scaffold placental tissue hybrid can be attached to atissue to be treated or can be attached to healthy tissue adjacent orsurrounding to the site of the injury, damage, or weakness. Anengineered scaffold placental tissue hybrid can be attached to muscle,tendon, ligament, joint, connective tissue, cartilage, bone, or thelike.

An engineered scaffold placental tissue steamer hybrid can be used totreat musculoskeletal tissue injury or degeneration in a subject. One ormore engineered tissue scaffolds can be combined with one or moreplacental tissue streamers to form an engineered scaffold placentaltissue steamer hybrid. The engineered scaffold placental tissue steamerhybrid can be contacted with a tissue to be treated (e.g., damaged,injured, or degenerated tissue). The engineered scaffold placentaltissue steamer hybrid can optionally be attached to the tissue to betreated or to healthy tissue adjacent to or surrounding the tissue to betreated.

Streamers

In an embodiment, placental tissue is cut into streamers to formplacental tissue streamers. In an embodiment, the streamer is any lengthranging from about 60 cm to about 1 cm, e.g. about 60, 50, 40, 30, 25,20, 15, 10, 8, 6, 5, 4, 3, 2, 1, 0.5, 0.1, cm or less. In an embodiment,the streamer is any width from about 20 cm to about 0.5 cm, e.g. about20, 18, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, 0.1, 0.05, 0.01 cm,or less. A streamer can have a longer length than the width, can besquare, or can be any other suitable shape. The streamer can be the fullthickness of the amniotic tissue or chorion membrane or portions orlayers of amniotic tissue, chorion membrane or umbilical cord. Aplacental streamer can be comprised of amnion, chorion, umbilical cordtissue, or combinations thereof. In an embodiment, a grouping ofstreamers is used where “grouping” represents a combination of more thanone streamers used together in the same tissue hybrid. In an embodiment,at least two placental tissue streamers (e.g., 2, 3, 4, 5, or more) areentwined together so as to form a placental tissue streamer rope. In anembodiment, at least two placental tissue streamers (e.g., 2, 3, 4, 5,or more) are stacked together so as to form a placental tissue streamerstack. The placental tissue streamers of the ropes of stacks maycomprise 1 or more sutures to hold the streamers together.

Placental Tissue Streamer Suture Hybrid

A placental tissue streamer can be surrounded by suture, as shown inFIG. 4. The combination of a placental tissue streamer surrounded bysuture is a placental tissue streamer suture hybrid. In an embodiment, asuture is a tubular sheath defining an empty bore. In an embodiment, thebore of the suture has a diameter of about 2 mm to about 0.4 mm, i.e.about 2.0, 1.8, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6,0.5, and 0.4 mm. A suture can be bioabsorbable or non-bioabsorbable.Where a suture is non-bioabsorable, it can provide permanent structuralsupport for the augmentation of tissue healing, or tissue regenerationor both. The suture can be a porous structure or a suture with gaps.That is, the suture surrounding the placental tissue streamer can havepores or gaps in the structure such that the placental tissue streameris retained within the suture, and such that biological agents ormolecules associated with the placental tissue streamer can move out ofthe suture and into the surrounding tissues. A porous or gappedstructure of a suture can allow for a faster delivery of regenerativebiomolecules to damaged or healthy tissue. A suture can be comprised of,for example, collagen or combinations of various polymers and collagensor any other suitable material.

One or more placental streamers can be threaded longitudinally throughthe opening or bore of the suture to form a placental tissue streamersuture hybrid. The placental tissue streamer suture hybrid can then beused to suture damaged, degenerated, injured, or healthy tissue throughmethods known in the art. A placental tissue streamer suture hybridsupplies a structural augmentation, biological augmentation, and/orsupport to heal, remodel, and/or regenerate damaged, injured, or healthytissues.

A placental tissue streamer suture hybrid can have “tails” of additionalsuture material on their ends. A placental tissue streamer suture hybridcan have a needle or anchor on one end of the suture.

The placental tissue streamer naturally contains regenerativebiomolecules important in healing, regeneration, and growth processes.The placental tissue streamer with its regenerative biomolecules insidethe suture bore can act as an augmentation boost for the repair ofdamaged or injured tissue or healthy tissue.

A placental tissue streamer suture hybrid can be used in primary repairof damaged tissues, such as tendon or ligament injury (e.g., rotatorcuff repair).

A placental tissue streamer suture hybrid can be used in augmentation ofrepaired or reconstructed tissue. In an embodiment, a method of surgicalrepair includes securing a reinforcement construct adjacent to arepaired or replacement ligament or tendon, wherein the reinforcementconstruct is secured by fixation devices, wherein a first fixationdevice and the second fixation device are secured adjacent to therepaired or replacement ligament's or tendons' attachment sites (e.g., aligament's insertion and origin points). In an embodiment, thereinforcement construct can be a placental tissue streamer suturehybrid. A reinforcement construct comprising a placental tissue streamercan be placed adjacent to repaired musculoskeletal tissue to supporthealing with both the structural support of a hybrid suture and thebiological augmentation of the placental membrane.

A placental tissue streamer suture hybrid can be attached to a tissue tobe treated or can be attached to healthy tissue adjacent to the site ofthe injury, damage, or weakness. A placental tissue streamer suturehybrid can be attached to muscle, tendon, ligament, joint, connectivetissue, cartilage, bone, or the like.

A placental tissue streamer suture hybrid can be loaded into a sutureanchor to form a placental tissue steamer suture hybrid anchor foraugmentation of the suture anchor to bone and soft tissue. An examplewould be a SutureBridge™ soft tissue reattachment or repair technique,which when loaded with the placental suture construct, and loaded withinthe suture anchor, becomes a biologically enhanced SutureBridge™.SutureBridge™ techniques are used, for example, in Achilles tendonreattachment following debridement. An hourglass pattern of sutures islaid over the distal end of the tendon. A multianchor (e.g., about 2, 3,4, 5, 6, or more) construct enables a greater area of compression forthe Achilles tendon on the calcaneus, improving stability and allowingfor earlier return to normal activities. See, e.g., FIG. 16.

Placental Tissue Patch Hybrid

A placental tissue patch hybrid comprising placental tissue (e.g.,placental tissue streamers) and a mesh construct can be used to deliverdifficult or delicate biologic constructs to a surgical repair,reconstruction, or regeneration site and maintain their presence at thesite post-operatively. In an embodiment, a placental tissue (e.g., aplacental tissue streamer) is interwoven in the mesh construct, ispresent in a compartment or pocket of the mesh construct, or attached onthe top, the bottom, or both the top and bottom of a mesh construct. Amesh construct can be a mesh biologic (i.e., a biomesh), that iscomprised of an organic biomaterial such as porcine dermis, porcinesmall intestine submucosa, bovine dermis or pericardium, and the dermisor fascia lata of a cadaveric human. These materials can be furtherprocessed to acellullar, porous extracellular matrix scaffolds ofcollagen and elastin. Some source growth factors can remain, whichattract endothelial cells and subsequent fibroblasts into the mesh. Amesh construct can also be a synthetic mesh.

A mesh construct can be a biocompatible fabric. The fabric can be, forexample, polymers of polyethylene, polypropylene, polyester (e.g.,polyethylene terephthalate), polyether ether ketone, polyacetal,polyurethane, polytetrafluoroethylene, polycarbonate, polysulfone,polyimide, copolymers thereof, or combinations thereof.

A placental tissue patch hybrid can also include bioresorbable syntheticpolymers, such as dextran, hydroxyethyl starch, derivatives of gelatin,polyvinylpyrrolidone, polyvinyl alcohol, poly[N-(2-hydroxypropyl)methacrylamide], poly(hydroxy acids), poly(epsilon-caprolactone),polylactic acid, polyglycolic acid, poly(dimethyl glycolic acid),poly(hydroxy butyrate), and similar copolymers.

A placental tissue patch hybrid can be any shape or size and cancomprise one or more pieces of placental tissue (e.g., one or moreplacental tissue streamers). For example the placental tissue patchhybrid can be a strip, rectangular, square, circular, ovoid or cut toany size or shape necessary (see e.g., FIG. 5). In an embodiment, aplacental tissue patch hybrid is shaped according to the anatomy for thesite of application.

A placental tissue hybrid patch can be adhered or attached to a surgicalrepair site. A surgical repair site can be a rotator cuff tendon repairor augmentation, an anterior cruciate ligament (ACL) repair, etc. In anembodiment, a partial thickness rotator cuff tear can be treated with aplacental tissue hybrid patch. In an embodiment, the patch is attachedover the repair site. For example, the patch can be positioned over therepair site and attached to adjacent muscles, ligaments, tendons, andbones. In an embodiment, a patch is attached via at least two flexiblestrands (e.g., suture, suture tape, or anchoring devices (e.g.,FiberTak® anchor) etc.) to the surrounding healthy tissue. In anembodiment, a placental tissue patch hybrid can be positioned over arotator cuff tendon repair. The shape of the patch can be adapted to theanatomy of the shoulder. Once positioned over the shoulder, the patchcan be sutured to the site via flexible strands sutured through theadjacent muscles and/or through suture anchors drilled into adjacentbones.

A placental tissue hybrid patch can be attached to a tissue to betreated, or can be attached to healthy tissue adjacent or surrounding tothe site of the injury, damage, or weakness. A placental tissue hybridpatch can be attached to muscle, tendon, ligament, joint, connectivetissue, cartilage, bone, or the like.

In another embodiment, a placental tissue patch hybrid can be wrappedaround a repaired ligament or other repaired, damaged, or degeneratedtissue. For example, a placental tissue patch hybrid can be wrappedaround a reattached ligament such as the ACL. The placental tissue patchhybrid can be wrapped so one lateral edge of the patch contacts itsopposite lateral edge. In another example, the two opposite lateraledges contact and there is overlap between the two lateral edges, whereone lateral edge is on top of the second lateral edge.

In an embodiment a placental tissue patch hybrid is used in meniscalrepair, or in the filling of meniscal loss.

In an embodiment, a placental tissue patch hybrid is used in rotatorcuff repair. A rotator cuff tendon, for example, a supraspinatus tendon,an infraspinatus tendon, a teres minor tendon, a subscapularis tendon,and/or a long head tendon, can be accessed and optionally debrided toremove any frayed intra-substance tissue from the torn or damagedtendon. The rotator cuff tendon can be pulled back into anatomicalposition if necessary, and a placental tissue patch hybrid can besecured to the tendon by, for example, sutures or suture anchors. Wherethe tendon is too short due to for example, degeneration or contracture,a placental tissue patch hybrid can be used as a bridge to span any gap.The placental tissue patch hybrid can be wrapped around the tendon orcan be placed over or along the tendon.

In an embodiment the top portion of the humerus can be decorticated.This can enhance biological incorporation and help with reattachment ofthe tendon. The tendon, the placental tissue patch hybrid, or both thetendon and placental tissue patch hybrid can be attached to the humerusby, for example, screws, suture anchors, adhesives, and the like.

The placental tissue patch hybrid can comprise one or more pockets orcompartments. One or more biological agents can be placed into the oneor more pockets or compartments. In an embodiment the placental tissuepatch hybrid can be wrapped around a tendon leaving one or more pocketsor compartments between the placental tissue patch hybrid and thetendon. One or more biological agents can be placed into the one or morepockets or compartments after the placental tissue patch hybrid iswrapped around the tendon.

In an embodiment, a placental tissue patch hybrid as disclosed hereincan be soaked in a solution comprising a biological agent such as: a)platelet rich plasma (PRP), b) bone marrow concentrate (BMC), c) growthfactors, d) stem cells, e) adipose derived growth factors, f) amnioticepithelial cells (AE) cells, g) umbilical cord-derived cells (UCD)cells, h) chorionic trophoblasts (CT), i) amnion derived or chorionderived mesenchymal stromal cells, or j) combinations thereof prior toimplantation. One or more of the biological agents (e.g., PRP or BMC)can be obtained from the patient to be treated. In an embodiment, asoaked placental tissue patch hybrid can be applied to a surgical repairsite, wherein a tendon, ligament, muscle, bone, or a combination thereofis repaired. A soaked placental tissue patch hybrid can be applied todamaged, injured, or degenerated tissue or any other tissue to betreated.

Patch Pockets and Contents of Pocket

In another embodiment, a placental tissue hybrid patch comprises one ormore compartments or pockets. The compartments can occur along theentire aspect of the placental tissue patch hybrid, especially the edgeswhere incorporation with native tissues can be important. In anembodiment, the compartments can be aligned in rows over the entire meshconstruct or over only a part of the mesh construct. The compartmentscan be any shape or size, for example, a strip, rectangular, square,circular, ovoid or any size or shape necessary. A compartment can beporous to allow the contents to migrate out of the compartment or toallow the contents contact with the tissue and/or the treatment site.

A compartment can be made in a mesh construct by sewing, securing, orfolding the mesh construct so that one or more compartments areavailable.

The compartment(s) are capable of containing a placental tissue (e.g., aplacental streamer) and/or a biological agent, which can migrate fromthe patch to the repair site over time. One or more of the biologicalagents (e.g., PRP or BMC) can be obtained from the patient to betreated. In a further embodiment, a placental tissue patch hybridcomprises a placental tissue interwoven within a mesh construct andincludes one or more compartments capable of containing a biologicalagent.

Patch/Wrap Uses

Placental tissue patch hybrid compositions can be used to replace tissueloss, such as in the case of massive irreparable rotator cuff tears,patellar tendon tears with tissue loss, or unreconstructable tissue lossof ligament, meniscus, glenoid or acetabular labrum. In such anembodiment, the mesh construct includes initial structural scaffoldingand strength, while the placental tissue and/or biological agent providebiologic stimulus for the ingrowth, regeneration, and reformation ofdamaged or absent musculoskeletal tissues. A specific example includes asuperior capsular reconstruction procedure using a placental tissuepatch hybrid composition instead of an allograft or xenograft tissue.

Placental tissue patch hybrid compositions can be used to augmentdamaged musculoskeletal tissues. Specific examples includenon-structural partial thickness rotator cuff tears, meniscal tears orloss, and patellar tendon rupture. In such cases the mesh constructsupplies mechanical strength while the placental tissue and/orbiological agent supplies biological healing augmentation to the injuredor degenerative tissue.

In an embodiment, a placental tissue patch hybrid can be used to augmentbiologic healing in the absence of structural repair. An example wouldbe a partial thickness rotator cuff tear, which does not requirestructural repair. The placental tissue patch hybrid, optionallycomprising a biological agent, can be placed over the damaged portion ofthe tendon and secured in place, allowing the elution and migration offactors from the placental tissue or biological agents to be deliveredto the site with added structural support. This can improve healingtimes or allow for faster rehabilitation programs.

A tissue hybrid can be used to repair, reconstruct, or regenerate tissuein a subject, The tissue hybrid can be a tissue with a midsubstance atleast one placental tissue streamer, wherein the placental tissuestreamer is located through the midsubstance or periphery of the tissuehybrid. A tissue hybrid can also be an engineered tissue placentaltissue hybrid, a suture placental tissue hybrid, or a placental tissuepatch hybrid. The injury or degeneration to the subject can comprisedamaged musculoskeletal tissue, and the repair or augmentation cancomprise rejoining the damaged musculoskeletal tissue and at least oneplacental tissue streamer to bone, tendon, ligament, connective tissue,cartilage, joint, or muscle of the subject.

In repairs or regeneration not requiring rejoining, the streamer,engineered tissue placental tissue hybrid, suture placental tissuehybrid, or placental tissue patch hybrid can be placed along or withinthe damaged tissue to augment healing, repair, reconstruction, orregeneration.

Kits

Compositions include kits comprising one or more of placental tissuestreamers, placental tissue, engineered scaffold placental tissuehybrid, suture placental tissue hybrid, placental tissue patch hybrids,or tissue hybrids. Kits can be self-contained, single use, and readilyavailable, which will provide some or all of the necessary materials forthe efficient use and delivery of the placental tissue, streamers, andtissue hybrids including, for example, buffers, biological agents,engineered tissue scaffolds, sutures, anchors, insertion devices, orneedles. In an embodiment, a kit includes all of the necessary materialsfor the efficient use and delivery of the placental tissue, streamers,and tissue hybrids including, for example, buffers, biological agents,engineered tissue scaffolds, sutures, anchors, insertion devices, orneedles, but does not include the placental tissue, streamers, or tissuehybrids

A kit can be, for example, designed for intraoperative delivery of aplacental tissue streamer directly into damaged or injured tissues, suchas a partial thickness rotator cuff tear or lateral epicondylitisdegeneration of the extensor carpi radialis brevis. Such a kit cancontain, for example, one or more placental tissue streamers (e.g.,about 0.5 cm×8 cm), a straight or curved suture lasso, a notched nitinol“plunger”, and one or more (e.g., 2, 4, 6) 4-0 LONG fiberloops.

In another example, a kit can be designed for delivery of a placentaltissue patch hybrid. Such a kit could contain a mesh patch (engineeredtissue scaffold) 5 cm×5 cm rectangular or custom shaped placental patch,1×8 cm, a red fiberstick tube (beveled on leading end, split on trailingend), a long (20 cm) nitinol loop, and (2) 4-0 LONG fiberloops andnitinol slotted inserter.

In another example, a kit can contain one or more components necessaryfor delivery of a placental tissue streamer suture hybrid. These kitscan be available in several sizes depending on the size of desiredsuture and the placental tissue streamer suture hybrid can beindependently inserted or loaded into a suture anchor. In an example, akit can contain one or more of placental tissue streamers (e.g., about 1cm×8 cm), 357 double tailed suture tube (e.g., about 8 cm long tube andabout 10 cm long tails), a thin plastic tube beveled on leading end andsplit on trailing end, a nitinol loop (e.g., about 20 cm long), 4-0 longFiberLoops® (continuous loop of a suture such as FiberWire® (e.g., amulti-strand long chain ultra-high molecular weight (UHMWEP) core with abraided jacket of polyester and UHMWEP), and multiple needle options.The plastic tube can be preloaded into the 357 double tailed suturetube.

A surgeon provided with a kit need only to cut the placental tissuestreamer, place a luggage tag suture through the placental tissuestreamer, and load the placental tissue streamer into the nitinol wire,or deliver the placental tissue streamer via loading onto a slottednitinol inserter.

In an embodiment, a placental tissue streamer suture hybrid kit can beused for direct injection/insertion of a placental tissue streamersuture hybrid under ultrasound guidance. A kit can contain, for example,one or more of placental tissue streamer (e.g., about 0.25 cm×8 cm), 14Gneedle or other sized needle (about 8 cm long), a notched plunger thatcan fixate the placental tissue streamer, that can be loaded into aneedle, and that can be held in place as needle is retracted

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art. As used herein, the singular forms “a,” “an,” and “the” includeplural referents unless the context clearly dictates otherwise. Forexample, reference to a “tissue” means one or more tissues. Further itcan include native biologic structure, autograft, allograft, xenograft,and engineered tissue scaffolds.

The terms “or” and “and/or” describe multiple components in combinationor exclusive of one another. For example, “x, y, and/or z” can refer to“x” alone, “y” alone, “z” alone, “x, y, and z,” “(x and y) or z,” “x or(y and z),” or “x or y or z.”

“Tissue hybrid” is a tissue comprising at least one placental tissuestreamer running through the midsubstance of the tissue, along the edgeof the tissue, or wrapped around the tissue. Examples of the tissue inthe tissue hybrid include, but are not limited to, muscle, tendon,ligament, cartilage, meniscus, intervertebral disk material, and otherconnective tissues. The tissue of the tissue hybrid can comprise an“outer layer” and a “midsubstance.” In an embodiment, the outer layerand the midsubstance can be made of the same type of tissue. In anembodiment, the outer layer and the midsubstance of the tissue can bemade of differing tissue types. After attachment to the patient, theouter layer acts as a covering to the midsubstance, separating themidsubstance from the environment in the patient cavity. The“midsubstance” of the tissue is comprised of a number of cells whichmake up the raw material of the tissue. An example of an outer layer isthe epimysium of a muscle while the muscle is an example of themidsubstance. Another example of an outer layer is the sheath of atendon while the tendon is an example of the midsubstance. Themidsubstance comprises a “midpoint,” which is substantially theintermediate or longitudinally central portion of the midsubstance.Neither the midsubstance nor the midpoint has to be the exact center ofthe tissue. A tissue hybrid also comprises an engineered scaffoldplacental tissue hybrid in contact with damaged, injured, or degeneratedtissue or in contact with a graft tissue. A tissue hybrid also comprisesa placental tissue in contact with damaged, injured, or degeneratedtissue or in contact with a graft tissue. A tissue hybrid also comprisessuture placental tissue hybrid in contact with damaged, injured, ordegenerated tissue or in contact with a graft tissue. A tissue hybridalso comprises placental tissue patch hybrid in contact with damaged,injured, or degenerated tissue or in contact with a graft tissue.

“Placental tissue” is tissue that is removed or separated from theplacenta. This includes amniotic tissue, chorionic tissue, and umbilicalcord tissue.

“Treatment,” “treating,” “repair,” “repairing,” “augmentation,” and“augmenting” refer to the process of administering or applying aplacental tissue to a patient at the site of a musculoskeletal tissuewound, weakness, or injury (i.e., a tissue to be treated) throughmethods disclosed herein.

“Musculoskeletal tissue injury” or “musculoskeletal tissue injuries”refer to injuries, damage, wear, aging, deterioration, or woundsoccurring to the soft tissue of the musculoskeletal system. Examples ofmusculoskeletal tissues include, but are not limited to, muscle, tendon,ligament, cartilage, meniscus, intervertebral disk, and other connectivetissue. Examples of musculoskeletal tissue injuries include, but are notlimited to, connective tissue injury, cartilaginous tissue injury,fibrous tissue injury, muscle tissue injury, and skeletal tissue injurysuch as sprains, strains, tears, partial tears, ruptures, and partialruptures as well as degenerative tendinopathies, and cartilage wear ofsoft tissues of the musculoskeletal system. Some specific examples ofcommon musculoskeletal injuries include, but are not limited to,tendinitis, partial thickness tears, tendinopathy, anterior cruciateligament rupture, Achilles tendon rupture or tendinopathy, rotator cufftear or tendinopathy, lateral epicondylitis, hamstring tear or strain,calf strains or tearing, bicep tendon rupture, meniscal tearing, medialmeniscal degeneration, degenerative disk disease, and “shoulderseparation” where the acromioclavicular (AC) joint is separated due totears in the AC ligament and/or the coracoclavicular ligament.

“Subject” and “patient” are used interchangeably herein and refer toboth human and nonhuman animals. The term “nonhuman animals” of thedisclosure includes all mammals, e.g., such as nonhuman primates, sheep,dog, cat, horse, cow, and the like.

“Amnion” and “amniotic tissue” are used interchangeably. Amnion is athin, cellular, extra-embryonic membrane that forms the inner membraneof a closed sac surrounding and protecting a mammalian embryo.Typically, the amnion is a tough, transparent, nerve-free, andnonvascular membrane consisting of two layers of cells, an inner,single-cell layer of ectodermal epithelium and an outer covering ofmesodermal, connective and specialized smooth muscular tissue. Afterbirth, the placenta is expelled and the amnion can be seen as a whitefringe lining of the inner cavity of the placenta. The amnion can beseparated from the placenta. The amniotic tissue is the lining of thefetal environment during gestation and separates the developing fetusfrom the mother in utero. Amniotic tissue is composed of a number oflayers and easily splits into an amnion layer and chorion layer, wherethe two layers are separated by a layer of Wharton's Jelly, agelatinous-like intermediate substance. The amnion layer is located onthe fetal side of the membrane and is principally composed of threetypes of material: collagen and extracellular matrix; viable tissuecells and cellular material; and regenerative molecules and growthfactors. The collagen and extracellular matrix materials of the amniotictissue form the structural component providing the tensile strength tothe amniotic tissue. The cellular material includes epithelial lining ofthe amnion facing the developing fetus, but also pluripotent stem cellsimportant in regenerating new cellular materials within the membranelining. Viable tissue cells present in the amniotic tissue includeepithelial stem cells and fibroblasts among others. Epithelial stemcells are native to the amniotic membrane and are biologically active inthe healing process. Fibroblasts are also present and provide lining andstrengthening of tissues. Regenerative biomolecules important in healingand growth processes are concentrated in the amniotic membrane. Suchbiomolecules include, but are not limited to, epidermal growth factor,transforming growth factor beta, fibroblast growth factors,platelet-derived growth factors, metalloproteinases, and tissueinhibitor of metalloproteinases.

“Chorion,” “chorionic tissue,” and “chorionic membrane” refer to tissuethat exists during pregnancy between the fetus and mother, whichcombines with the amnion to form the amniotic sac. Chorion is formed byextraembryonic mesoderm and consists of two layers, an outer layerformed by trophoblast, and an inner layer formed by somatic mesoderm.Chorion is used herein to refer to the outer trophoblast layer, theinner somatic mesoderm layer, or both layers together.

“Umbilical cord tissue” refers to the tissue removed from the umbilicalcord, a structure which connects the fetus to the placenta and developsfrom the yolk sac and allantois of the early fetus. The umbilical cordcomprises an outer connective tissue layer, blood vessels (at least onevein and at least one artery), and wharton's jelly. In an embodiment,the blood vessels are removed from the umbilical cord's outer connectivetissue layer. In an embodiment, all parts of the umbilical cord areharvested and used, including the blood vessels.

“Streamer” of placental tissue refers to a strip of placental tissue.The strip of placental tissue comprises amniotic membrane tissue,chorion membrane tissue, umbilical cord tissue, and combinationsthereof. “Streamer,” “strip,” “band,” and “strand” can be usedinterchangeably. A streamer is any length ranging from about 60 cm toabout 1 cm, e.g. about 60, 50, 40, 30, 25, 20, 15, 10, 8, 6, 5, 4, 3, 2,1 cm or less. The streamer is any width from about 20 cm to about 0.5cm, e.g. about 20, 18, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5 cm orless. The streamer can be the full thickness of the placental tissue,amniotic tissue, chorion tissue, or umbilical cord tissue. As usedherein, “a grouping of streamers” is used where “grouping” represents acombination of two or more streamers used together in the same tissuehybrid.

A “placental tissue streamer rope” is at least two placental tissuestreamers (e.g., 2, 3, 4, 5, or more) that are entwined together so asto form a rope-like composition. A placental tissue streamer rope cancomprise 1 or more sutures to hold the streamers together in therope-like form.

A “placental tissue streamer stack” is at least two placental tissuestreamers (e.g., 2, 3, 4, 5, or more) that are stacked together so as toform a stack-like composition. The placental tissue streamer stack cancomprise 1 or more sutures to hold the streamers together in thestack-like form.

“Placental tissue streamer attachment site” refers to the location ofwhere the placenta tissue streamer is to be attached. The placentaltissue streamer attachment site can be in a tissue hybrid, or can belocated in healthy tissue adjacent to the site of the injury, damage, orweakness. A placental tissue streamer attachment site can be located inmuscle, tendon, ligament, joint, connective tissue, cartilage, bone, orthe like. In an embodiment, the placental tissue streamer attachmentsite is located outside of the tissue hybrid in healthy tissue adjacentto the site of the injury, weakness, or damage.

“Tissue attachment site” refers to the location where tissue isattached. The tissue attachment site may be the same as the placentaltissue streamer attachment site; however, the tissue attachment site maybe a different site than the placental tissue streamer attachment site.For example, in a repair of a partially ruptured Achilles tendon, theplacental tissue streamer can be attached in two places, at thecalcaneus and the gastrocnemius, so there are two placental tissuestreamer attachment sites. The Achilles tendon can be sutured back toitself at the site of injury, closing the gap left by the tear. Wherethe Achilles tendon was sutured back together is the tissue attachmentsite.

A “placental tissue patch hybrid” comprises placental tissue and a meshconstruct. The placental tissue can be interwoven in the mesh construct,can be present in a compartment or pocket of the mesh construct, or canbe attached on the top, the bottom, or both the top and bottom of a meshconstruct. A mesh construct can be a mesh biologic (i.e., a biomesh) ora synthetic mesh.

A “placental tissue streamer suture hybrid” is a placental tissuestreamer surrounded by a bioabsorbable or non-bioabsorbable suture. Thesuture can be a tubular sheath defining a bore wherein a placentaltissue streamer is threaded through the bore.

“Autograft” refers to a tissue obtained from the patient's body and thattissue is placed back into the same patient's body. “Allograft” refersto a body tissue obtained from one patient and grafted to a geneticallydissimilar patient of the same species. Allograft materials can beobtained from mammalian sources, including, but not limited to, equine,canine, feline, bovine, porcine, sheep, or goat, and human sources.“Xenograft” refers to a tissue or organ obtained from one species andplaced into an individual of another species. “Engineered tissuescaffold” refers to a material created to provide structural support forcell attachment and subsequent tissue development.

“Biopreserved tissue” refers to tissue that has been recovered andtreated as to keep the integrity and functionality of cells, tissues,and organs held outside of their native environment for extended storagetimes.

“Pre-repair,” “pre-augmentation,” “post-repair,” and “post-augmentation”refer to the timing of when the placental tissue streamers are threadedthrough tissue. “Pre-repair” and “pre-augmentation” refer to threadingthe placental tissue streamer through the midsubstance of the tissuebefore a damaged tissue is repaired. This also includes using a tissuegraft and threading the placental tissue streamer through themidsubstance of the tissue graft before attaching the tissue graft inthe subject. “Post-repair” refers to the damaged tissue being repairedor augmented before the threading of the placental tissue streamers. Forexample, an Achilles tendon can be repaired or augmented through methodsknown in the art, and then at least one placental tissue streamer isthreaded through the repaired Achilles tendon.

“Tissue regeneration” is the renewal and growth of tissues through, forexample, proliferation of cells.

“Tissue repair” is the restoration of tissue architecture and functionafter injury or disease.

“Tissue reconstruction” is the use of allograft tissues, autografttissues, xenograft tissue, or engineered tissue scaffolds to reinforceand repair tissue.

EXAMPLES

The examples that follow are illustrative of specific methods anddevices disclosed herein and various uses thereof. They are set forthfor explanatory purposes only, and are not to be taken as limiting.

Example 1

Rotator Cuff Repair

One exemplary method was the repair of a rotator cuff of a humancadaver. A full thickness tear to the supraspinatus tendon of therotator cuff was created to mimic a natural tear. The tear was thenrepaired by placing an amniotic streamer in the midsubstance of thesupraspinatus tendon and running into the supraspinatus tissue. Thestreamer was attached to the supraspinatus muscle at one end and to thehead of the humerous at the other. The supraspinatus tendon was thensutured through methods known in the art.

Example 2 Ex-vivo Amnion Wrapping Procedure

An anterior cruciate ligament graft was prepared for insertion into ajoint (FIG. 6). It should be noted that this methodology can also beused in soft tissue grafts also (e.g., hamstring grafts). An allograftpatellar tendon was wrapped in an amnion membrane (FIGS. 7-11). Twosutures were used to connect the graft to the amnion membrane at eitherend (FIGS. 7 and 8) at one end of the graft. The graft was wrapped inamnion multiple times creating multiple layers (FIG. 9). One cerclagestitch was placed at either end of the amnion membrane after wrapping.(FIG. 10). A running stitch was also placed at the end of the amnionmembrane (FIG. 11). The two cerclage stitches and the running stitchcreated multiple water-tight compartments (cells), which can bedependent on the number of layers of wrapping. The water-tightcompartments were filled with a biological agent after implantation ofthe graft. (FIGS. 12-14).

In Vivo Biologic Injection

After the graft was inserted into the joint and secured (FIG. 12), thearthroscopic fluid was evacuated from the joint. The graft haswater-tight compartments of the amnion wrapped graft. Whole blood wasinjected into the water-tight compartments of the graft to testbiological fluid retention in the joint.

Having described the methods and devices in detail and by reference tospecific examples thereof, it will be apparent that modifications andvariations are possible without departing from the scope of the methodsand devices defined in the appended claims. More specifically, althoughsome aspects of the methods and devices are identified herein asparticularly advantageous, it is contemplated that the methods andcompositions are not limited to these particular aspects.

What is claimed is:
 1. A method of anterior cruciate ligament repaircomprising: a) wrapping amnion tissue around a tissue graft to form awrapped graft; b) placing at least one cerclage stitch at either end ofthe amnion tissue and one running stitch at the end of the wrapped graftto form a water-tight compartment; c) inserting the wrapped graft into aknee joint; and d) adding platelet rich plasma or bone marrowconcentrate to the water-tight compartment between the amnion tissue andthe tissue graft.
 2. The method of claim 1, wherein the amnion iswrapped more than once around the tissue graft.
 3. A method of ligamentrepair comprising: a) wrapping placental tissue around a tissue graft toform a wrapped graft; b) placing at least one stitch at either end ofthe placental tissue and one stitch at the end of the wrapped graft toform at least one water-tight compartment; and c) adding a biologicalagent to the at least one water-tight compartment.
 4. The method ofclaim 3, wherein the at least one water-tight compartment is between theplacental tissue and the tissue graft.
 5. The method of claim 3, whereinthe biological agent is platelet rich plasma, bone marrow concentrate,viscous amnion, a growth factor, or stem cells.
 6. The method of claim3, wherein the placental tissue is wrapped around the tissue graft morethan once.
 7. The method of claim 6, wherein the biological agent isadded to a compartment between different layers of the placental tissue.8. The method of claim 3, wherein the placental tissue is amnion,chorion, or umbilical cord.
 9. The method of claim 3, wherein theplacental tissue is a placental tissue streamer, an engineered scaffoldplacental tissue hybrid, or a suture placental tissue hybrid.
 10. Themethod of claim 3, further comprising inserting the wrapped graft into aknee joint before adding the biological agent to the at least onewater-tight compartment.
 11. The method of claim 3, further comprisinginserting the wrapped graft into a knee joint after adding thebiological agent to the at least one water-tight compartment.
 12. Themethod of claim 3, wherein the stitch at the end of the wrapped graft isa running stitch.
 13. The method of claim 3, wherein the stitches ateither end of the placental tissue are cerclage stitches.
 14. The methodof claim 3, wherein the tissue graft is a tissue hybrid.
 15. The methodof claim 1, where in the tissue graft is a patellar tendon, a hamstringgraft, or a quadriceps tendon graft.
 16. The method of claim 3, where inthe tissue graft is a patellar tendon, a hamstring graft, or aquadriceps tendon graft.